Utilisation of the Prestwick Chemical Library to identify drugs that inhibit the growth of mycobacteria.

Tuberculosis (TB) is an infectious bacterial disease that kills approximately 1.3 million people every year. Despite global efforts to reduce both the incidence and mortality associated with TB, the emergence of drug resistant strains has slowed any progress made towards combating the spread of this deadly disease. The current TB drug regimen is inadequate, takes months to complete and poses significant challenges when administering to patients suffering from drug resistant TB. New treatments that are faster, simpler and more affordable are urgently required. Arguably, a good strategy to discover new drugs is to start with an old drug. Here, we have screened a library of 1200 FDA approved drugs from the Prestwick Chemical library using a GFP microplate assay. Drugs were screened against GFP expressing strains of Mycobacterium smegmatis and Mycobacterium bovis BCG as surrogates for Mycobacterium tuberculosis, the causative agent of TB in humans. We identified several classes of drugs that displayed antimycobacterial activity against both M. smegmatis and BCG, however each organism also displayed some selectivity towards certain drug classes. Variant analysis of whole genomes sequenced for resistant mutants raised to florfenicol, vanoxerine and pentamidine highlight new pathways that could be exploited in drug repurposing programmes

Case report of research data management support services in Australian university libraries

本稿は，2019年9 月に訪問したシドニー大学図書館（University of Sydney Library），ニューサウスウェールズ大学図書館（University of New South Wales Library）， メルボルン大学図書館（University of Melbourne Library），モナシュ大学図書館（Monash University Library），でのインタビュー調査に基づきオーストラリアの大学図書館における研究データ管理支援サービスについて報告する。調査から，大学によって使用しているツールや重点を置いているサービスは違うが，研究データのライフサイクルに即したサービスを展開していることがわかった

Data from: Biofilm morphotypes and population structure among Staphylococcus epidermidis from commensal and clinical samples

Bacterial species comprise related genotypes that can display divergent phenotypes with important clinical implications. Staphylococcus epidermidis is a common cause of nosocomial infections and, critical to its pathogenesis, is its ability to adhere and form biofilms on surfaces, thereby moderating the effect of the host’s immune response and antibiotics. Commensal S. epidermidis populations are thought to differ from those associated with disease in factors involved in adhesion and biofilm accumulation. We quantified the differences in biofilm formation in 98 S. epidermidis isolates from various sources, and investigated population structure based on ribosomal multilocus typing (rMLST) and the presence/absence of genes involved in adhesion and biofilm formation. All isolates were able to adhere and form biofilms in in vitro growth assays and confocal microscopy allowed classification into 5 biofilm morphotypes based on their thickness, biovolume and roughness. Phylogenetic reconstruction grouped isolates into three separate clades, with the isolates in the main disease associated clade displaying diversity in morphotype. Of the biofilm morphology characteristics, only biofilm thickness had a significant association with clade distribution. The distribution of some known adhesion-associated genes (aap and sesE) among isolates showed a significant association with the species clonal frame, with the exception of. These data challenge the assumption that biofilm-associated genes, such as those on the ica operon, are genetic markers for less invasive S. epidermidis isolates, and suggest that phenotypic characteristics, such as adhesion and biofilm formation, are not fixed by clonal descent but are influenced by the presence of various genes that are mobile among lineages

Genome assemblies

Assembled genomes used in this study to identify rMLST, virulence and biofilm-associated gene sequences

Non-Replicating <i>Mycobacterium tuberculosis</i> Elicits a Reduced Infectivity Profile with Corresponding Modifications to the Cell Wall and Extracellular Matrix

<div><p>A key feature of <i>Mycobacterium tuberculosis</i> is its ability to become dormant in the host. Little is known of the mechanisms by which these bacilli are able to persist in this state. Therefore, the focus of this study was to emulate environmental conditions encountered by <i>M. tuberculosis</i> in the granuloma, and determine the effect of such conditions on the physiology and infectivity of the organism. Non-replicating persistent (NRP) <i>M. tuberculosis</i> was established by the gradual depletion of nutrients in an oxygen-replete and controlled environment. In contrast to rapidly dividing bacilli, NRP bacteria exhibited a distinct phenotype by accumulating an extracellular matrix rich in free mycolate and lipoglycans, with increased arabinosylation. Microarray studies demonstrated a substantial down-regulation of genes involved in energy metabolism in NRP bacteria. Despite this reduction in metabolic activity, cells were still able to infect guinea pigs, but with a delay in the development of disease when compared to exponential phase bacilli. Using these approaches to investigate the interplay between the changing environment of the host and altered physiology of NRP bacteria, this study sheds new light on the conditions that are pertinent to <i>M. tuberculosis</i> dormancy and how this organism could be establishing latent disease.</p></div

Histopathological changes in guinea pig lung following aerosol challenge with <i>M. tuberculosis</i> cultured from different growth phases of nutrient starvation at days 16 and 42 post challenge.

<p>H&E. Magnification bar, 500 µm.</p

The mutant frequency of <i>Mycobacterium tuberculosis</i> H37Rv growing at either a fast growth rate or a slow growth rate in response to isoniazid exposure.

<p>The mutant frequency of <i>Mycobacterium tuberculosis</i> H37Rv growing at either a fast growth rate (Panel A, solid lines; circles: Culture INH23.2 & triangles: Culture INH23.3) or a slow growth rate (Panel B solid lines; circles: Culture INH69.2 & triangles: Culture INH69.3) for at least 7 MGT in response to isoniazid (0.5 mg L^-1) added at 0h and continuously throughout culture. Each line represents the mutant frequency from an individual chemostat culture. The dotted lines in each case are control cultures without isoniazid addition</p

Genes that were more highly expressed during fast growth compared with slow growth prior to isoniazid addition.

<p>Genes that were more highly expressed by at least two-fold during fast growth compared with slow growth prior to isoniazid addition. AS and S indicate whether the higher levels of transcript were detected in the sense or antisense strand respectively.</p><p>Genes that were more highly expressed during fast growth compared with slow growth prior to isoniazid addition.</p